Abstract 106P
Background
Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs consisting of a tumor-targeting small molecule ligand, a cleavable linker, and a potent cytotoxic payload. We have recently developed a novel small organic ligand (named OncoFAP) for Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most solid human malignancies. Nuclear medicine studies have validated the tumor-targeting performance of OncoFAP. In this work, we used the OncoFAP targeting moiety to create SMDCs for the delivery of cytotoxic payloads to solid tumors.
Methods
We developed a series of SMDC derivatives bearing MMAE as potent cytotoxic payload (tubulin poison) conjugated to OncoFAP by dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. We quantified the tumor accumulation of free MMAE released by the different SMDCs and benchmarked the new FAP-cleavable conjugates against OncoFAP-MMAE conjugates displaying linker modules widely used in approved and clinical stage Antibody-Drug Conjugates. We further evaluated the therapeutic efficacy of the conjugates in preclinical models of cancer.
Results
Among the evaluated compounds, OncoFAP-GlyPro-MMAE showed the highest and most selective release of MMAE at the site of disease, with a tumor-to-kidney ratio of ∼7-to-1 at 6 hours and of ∼16-to-1 at 24 hours post-injection. A higher release of payload resulted in a more potent tumor control in preclinical models of cancer. Potent anti-cancer efficacy was observed both in models with cellular expression of FAP and in patient-derived xenograft models which mirror the tumor architecture seen in most human cancer patients.
Conclusions
OncoFAP-GlyPro-MMAE emerged as a highly promising candidate for the selective delivery and release of the MMAE cytotoxic payload at the site of disease. The compound has been selected for clinical development and is planned to enter phase I studies shortly.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Philochem AG.
Funding
Philochem AG.
Disclosure
J.C. Mock: Financial Interests, Personal, Full or part-time Employment: Philochem AG, Philogen S.p.A. A. Galbiati, M. Bocci, A. Zana, E. Gilardoni, S. Cazzamalli: Financial Interests, Personal, Full or part-time Employment: Philochem AG. D. Neri: Financial Interests, Personal, Ownership Interest: Philogen S.p.A.; Financial Interests, Personal, Leadership Role: Philogen S.p.A., Philochem AG; Financial Interests, Personal, Member of Board of Directors: Philogen S.p.A.